The background of this invention will address Malarial Infection and Resistance to Antimalarial Drugs and Compounds.
Malarial Infection
Malaria is an infectious disease caused by mosquito-borne Plasmodium parasites affecting humans and other animals. The disease is prevalent in the tropical and subtropical regions of the world, particularly in areas around the equator. Malaria symptoms typically include chills, fever, fatigue, headaches, nausea or vomiting, and severe cases can result in seizures, coma, or death. More than 200 million cases of malaria occur worldwide annually resulting in over 500,000 deaths each year. The disease is most commonly transmitted by a bite from an infected Anopheles mosquito. The mosquito's saliva introduces the parasites into a person or animal's blood. Once in the bloodstream, the parasites travel to the liver where they mature and reproduce.
Malaria parasites belong to the genus Plasmodium (phylum Apicomplexa) and there are five known species of Plasmodium that can infect and be spread by humans. Plasmodium falciparum is the most common species identified in humans, followed by P. vivax. Less commonly isolated species are P. malariae, P. ovale, and P. knowlesi. P. falciparum generally accounts for the majority of deaths while P. vivax, P. ovale, and P. malariae usually causing a milder form of the disease.
Malaria infection develops via two phases: the first phase involves the liver, and the second phase involves the red blood cells. When an infected mosquito bites an individual, the Plasmodium sporozoites from the mosquito's saliva enter the bloodstream, and migrate to the liver. Once the sporozoites infect the liver cells, they multiply over a period of 8-30 days, eventually causing the infected liver cells to rupture. The parasites then return to the bloodstream, where they infect the red blood cells.
Because the malaria parasite resides for most of its human life cycle within the liver and blood cells, it is somewhat unnoticed by immune surveillance, and is consequently protected from the body's immune system. However, circulating infected blood cells are destroyed in the spleen. In addition to this, the P. falciparum parasite secrete adhesive proteins on the surface of the infected red blood cells, causing the blood cells to adhere to the walls of small blood vessels, further sequestering the parasite from the general circulation and the spleen.
Resistance to Antimalarial Drugs
As yet, there are no effective vaccines against malaria, and control of the disease depends upon antimalarial drugs that kill parasites inside the body. Diagnosis of malaria is made by microscopic examination of blood, or with antigen-based rapid diagnostic tests. Once diagnosed, the recommended treatment is a combination of antimalarial medications including chloroquine, quinine, mefloquine, amodiaquin, primaquine, pyrimethamine, sulfonamides, sulfones, dihydrofolate reductase inhibitors, and tetrandine, as well as others.
Recent decades have seen the emergence of parasites resistant to standard drug therapies, and drug resistance is increasingly a problem in malaria treatment. Antimalarial drugs, such as cryptolepine and artemisinin, are often initially effective; however, the parasites that cause the disease continuously evolve and become resistant to the drugs. Resistance is now common against most classes of antimalarial drugs. Treatment of resistant strains has become progressively more reliant on a few remaining drugs, and continued use of these drugs will increase the incidence of resistance. P. falciparum in particular has developed resistance to nearly all of the currently available antimalarial drugs.
Compounds
Furthermore, many effective antimalarial drugs include an organic peroxide moiety, which generally includes two carbon atoms linked by the peroxide bond atoms. The known methods for constructing the organic peroxide bond are highly inefficient and ineffective. For example, one method for constructing the organic peroxide moiety includes the coupling reaction of oxygen radicals to form a peroxide bond. The oxygen free radicals are highly reactive, which makes unwanted side reactions difficult to control.
The known methods for constructing the organic peroxide moiety require either a special substrate or special conditions. Moreover, none of them can be integrated with carbazole moeities and the classic peroxide oxidant to give N-(α-peroxy)carbazole.